Acute leukemia, including acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL), is characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. Despite the great progress made in the treatment outcome of AML, more than half of young adult patients and about 90% of older patients still die from their disease. While cure is achieved in more than 80% of affected children with ALL, only 20-40% of adults are cured. Therefore, there is an urgent need to develop new therapeutic approaches for both AML and ALL. The human murine double minute 2 (MDM2) protein is an oncogene and is an attractive cancer therapeutic target. Several small-molecule MDM2 inhibitors are currently in clinical trials for cancer treatment, including AML. Despite their potential promise, small-molecule MDM2 inhibitors can dramatically upregulate MDM2 expression, which may limit their potential clinical efficacy and have unwanted deleterious effects due to the oncogenic activity of MDM2 protein. New therapeutic strategies are therefore needed to more effectively target MDM2 toward improving efficacy, reducing side effects and overcoming resistance. We have designed proteolysis-targeting chimera (PROTAC) small-molecules to efficiently induce degradation of MDM2 protein (hereafter called MDM2 degraders) and investigated their therapeutic potential and mechanism of action in acute leukemia models in vitro and in vivo. Our preliminary data strongly suggest that targeting MDM2 degradation is a novel and very exciting therapeutic approach for the treatment of acute leukemia. Toward developing a novel therapy for the treatment of acute leukemia by targeting MDM2 degradation, we propose to perform the following specific Aims: Aim 1: Design and synthesis of new MDM2 degraders to further optimize their cellular potencies, pharmacokinetics and in vivo efficacy. Aim 2: Investigation of their in vitro activity and mechanism of action using human ALL and AML cell lines and acute leukemia samples from patients. Aim 3: Determination of their metabolic stability, pharmacokinetics, in vivo anticancer activity in mouse models of human acute leukemia and their potential toxicity in mice. To the best of our knowledge, our laboratory is the first to develop PROTAC small-molecule MDM2 degraders. Successfully performed, this project will bring the first-in-class, highly optimized MDM2 small- molecule degrader into advanced preclinical development and clinical trials as a new therapy for the treatment of acute leukemia.